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Neutralizing antibody responses induced by HIV-1 envelope glycoprotein SOSIP trimers derived from elite neutralizers

Neutralizing antibody responses induced by HIV-1 envelope glycoprotein SOSIP trimers derived from elite neutralizers
Neutralizing antibody responses induced by HIV-1 envelope glycoprotein SOSIP trimers derived from elite neutralizers

The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1 infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Its structure at 4.3 Å resolution was overall similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous Tier-2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009 and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers.IMPORTANCE Elite neutralizers, i.e. individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.

Env trimer, SOSIP trimer, elite neutralizer, immunogenicity, neutralizing antibodies
0022-538X
Schorcht, Anna
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van den Kerkhof, Tom L G M
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Cottrell, Christopher A
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Allen, Joel D
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Torres, Jonathan L
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Behrens, Anna-Janina
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Schermer, Edith E
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Burger, Judith A
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de Taeye, Steven W
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de la Peña, Alba Torrents
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Bontjer, Ilja
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Gumbs, Stephanie
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Ozorowski, Gabriel
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LaBranche, Celia C
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de Val, Natalia
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Yasmeen, Anila
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Klasse, Per Johan
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Montefiori, David C
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Moore, John P
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Schuitemaker, Hanneke
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Crispin, Max
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van Gils, Marit J
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Ward, Andrew B
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Sanders, Rogier W
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Schorcht, Anna
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van den Kerkhof, Tom L G M
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Cottrell, Christopher A
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Allen, Joel D
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Torres, Jonathan L
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Behrens, Anna-Janina
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Schermer, Edith E
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Burger, Judith A
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de Taeye, Steven W
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de la Peña, Alba Torrents
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Bontjer, Ilja
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Gumbs, Stephanie
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Ozorowski, Gabriel
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LaBranche, Celia C
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de Val, Natalia
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Yasmeen, Anila
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Klasse, Per Johan
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Montefiori, David C
e1f1e5f0-7bed-4994-81e2-7f1e0ff5663b
Moore, John P
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Schuitemaker, Hanneke
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Crispin, Max
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van Gils, Marit J
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Ward, Andrew B
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Sanders, Rogier W
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Schorcht, Anna, van den Kerkhof, Tom L G M, Cottrell, Christopher A, Allen, Joel D, Torres, Jonathan L, Behrens, Anna-Janina, Schermer, Edith E, Burger, Judith A, de Taeye, Steven W, de la Peña, Alba Torrents, Bontjer, Ilja, Gumbs, Stephanie, Ozorowski, Gabriel, LaBranche, Celia C, de Val, Natalia, Yasmeen, Anila, Klasse, Per Johan, Montefiori, David C, Moore, John P, Schuitemaker, Hanneke, Crispin, Max, van Gils, Marit J, Ward, Andrew B and Sanders, Rogier W (2020) Neutralizing antibody responses induced by HIV-1 envelope glycoprotein SOSIP trimers derived from elite neutralizers. Journal of Virology, 94 (24), [e01214-20]. (doi:10.1128/JVI.01214-20).

Record type: Article

Abstract

The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1 infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Its structure at 4.3 Å resolution was overall similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous Tier-2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009 and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers.IMPORTANCE Elite neutralizers, i.e. individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.

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Accepted/In Press date: 30 September 2020
e-pub ahead of print date: 30 September 2020
Additional Information: Copyright © 2020 Schorcht et al.
Keywords: Env trimer, SOSIP trimer, elite neutralizer, immunogenicity, neutralizing antibodies

Identifiers

Local EPrints ID: 445206
URI: http://eprints.soton.ac.uk/id/eprint/445206
ISSN: 0022-538X
PURE UUID: 2cb3faae-1fdb-45b3-9800-786e7fa95f27
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

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Date deposited: 25 Nov 2020 17:31
Last modified: 18 Feb 2021 17:31

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Contributors

Author: Anna Schorcht
Author: Tom L G M van den Kerkhof
Author: Christopher A Cottrell
Author: Joel D Allen
Author: Jonathan L Torres
Author: Anna-Janina Behrens
Author: Edith E Schermer
Author: Judith A Burger
Author: Steven W de Taeye
Author: Alba Torrents de la Peña
Author: Ilja Bontjer
Author: Stephanie Gumbs
Author: Gabriel Ozorowski
Author: Celia C LaBranche
Author: Natalia de Val
Author: Anila Yasmeen
Author: Per Johan Klasse
Author: David C Montefiori
Author: John P Moore
Author: Hanneke Schuitemaker
Author: Max Crispin ORCID iD
Author: Marit J van Gils
Author: Andrew B Ward
Author: Rogier W Sanders

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